A novel synthetic approach to the racemic Neuraminidase inhibitor Peramivir

Abstract

An advanced intermediate in the synthesis of the racemic Neuraminidase inhibitor Peramivir was synthesised in a new and versatile manner starting from a stereoselective 1,3-dipolar cycloaddition reaction between the nitrile oxide deriving from 2-ethylbutanal and the commercially available and inexpensive bicyclo[2.2.1]hepta-2,5-diene. The reaction mainly afforded the exo-isoxazolino-norbornene derivative from which the oxidative cleavage of the carboncarbon double bond followed by subsequent dehydration led to the corresponding anhydride intermediate. Amines and alcohols were used as nucleophiles for opening the anhydride, with amines providing the better results. Both the monoester–monoacid and the monoester–monoamide were transformed into the monoester–monoamino intermediate from which the synthesis continued using previously published methods. In the best protocol, the total yield of this key intermediate was increased up to 17% from bicyclo[2.2.1]hepta-2,5-diene.